The overall goal of this research proposal is to understand mechanisms of brain injury and clinical progression, as well as introduce new imaging biomarkers and therapeutic targets in children with unilateral Sturge-Weber syndrome (SWS). During the first cycle of funding, our longitudinal approach to the assessment of structural, metabolic and neuro-cognitive abnormalities in SWS defined the time frame of disease progression and imaging correlates of neuro-cognitive deficit. The main focus of our continuing studies is to understand the specific mechanisms leading to highly variable neurological and cognitive outcomes in SWS despite limited initial brain involvement. Our general hypothesis is that the cerebral vascular malformation, rather than the traditional view as being static, undergoes proliferative transformation in patients with a progressive course. This hypothesis is based upon our novel preliminary data that the angioma shows increased protein synthesis on [11C]leucine PET and abnormal expression of proliferation markers and angiogenic proteins in vascular endothelial cells in resected tissues. The second major finding during the first cycle of finding was evidence for a perfusion/metabolic mismatch in the cortex, due to perfusion changes measured by MR Perfusion Weighted Imaging (PWI) extending beyond the MR structural and PET glucose metabolic abnormalities. Finally, we found that white matter volume loss and abnormal water diffusion were related to cognitive deficits in our sample of children with SWS. To study these mechanisms of disease progression, we will combine advanced MRI and PET techniques, as well as immunohistochemistry studies from resected tissue to address three aims: (1) To study protein synthesis, increased proliferative activity and expression of angiogenic factors in the region of the angioma, and to determine if increased protein synthesis measured by PET is associated with progressive cognitive and neurological deficits in children with unilateral SWS. (2) To evaluate early cerebral hemodynamic changes and their significance for metabolic and neurological progression. (3) To evaluate white matter diffusion abnormalities and their contribution to cognitive outcome. The proposed studies are expected to identify novel therapeutic targets in SWS. Most importantly, proliferative leptomeningeal angiomas may be amenable to anti-angioma therapies, which would be a major breaktrough in the clinical management of SWS. The applied advanced imaging techniques can also be used to monitor future therapeutic trials aimed at preventing ischemic cortical damage and white matter injury. In addition, the proposed studies will serve the wider medical community by establishing the clinical use and evaluate the functional and clinical correlates of advanced MRI and PET techniques in children, and better understanding mechanisms of progressive brain damage due to chronic ischemia. PUBLIC HEALTH RELEVANCE: The goal of this research project is to understand mechanisms of disease progression in children with Sturge-Weber syndrome. We will apply advanced neuroimaging techniques, including various magnetic resonance imaging (MRI) and positron emission tomography (PET) methods, combined with immunohistochemistry studies of resected brain and angioma tissues, to study proliferative changes and abnormal angiogenesis in the leptomeningeal angioma, as well as structural, perfusion, and metabolic changes in the underlying cortex and white matter. The results will introduce novel, more accurate diagnostic tests and also identify new therapeutic targets to improve the outcome of this often devastating disease.